New perspective on the nutritional approach to cancer-related anorexia/cachexia: Preliminary results of a randomised phase III clinical trial with five different arms of treatment

Cancer-related anorexia/cachexia syndrome (CACS) is a multifactorial syndrome characterised by tissue wasting, particularly lean body mass (LBM), metabolic alterations, fatigue, anorexia and reduced food intake. In April 2005 we started a phase III randomised study to establish the most effective and safest treatment for CACS addressing as primary endpoints: LBM, resting energy expenditure (REE), total daily physical activity, interleukin (IL)-6 and tumour necrosis factor (TNF)-α levels, and fatigue. According to the statistical design the sample size was 475 patients (95 per arm). Eligibility criteria: histologically confirmed tumours of any site; weight loss -5% in the last 3 months and/or abnormal laboratory values; life expectancy >4 months. Patients were treated with either antineoplastic therapy or supportive care. All patients received as basic oral treatment polyphenols plus alpha lipoic acid plus carbocysteine plus vitamins A, C and E. Patients were then randomised to one of the following 5 arms: (1) medroxyprogesterone acetate (MPA)/megestrol acetate (MA); (2) pharmaconutritional support containing eicosapentaenoic acid (EPA); (3) l-carnitine; (4) thalidomide; and (5) a combination of all the above agents. Treatment duration was 4 months. Interim analyses were planned after every 100 randomised patients. In September 2008, 280 patients were randomised and 240 were evaluable: M/F 167/113, mean age 62 years (range 30-84), 96% stage IV. A first interim analysis on 125 patients showed a worsening of LBM, REE and fatigue in arm 2 in comparison to the others and therefore it was withdrawn from the study. A second interim analysis after the enrolment of 204 patients showed that arm 1 was clearly significantly less effective than the others for primary efficacy endpoints, therefore it was withdrawn from the study. Statistical analysis in September 2008 showed a significant improvement of LBM (by dual X-ray energy absorptiometry), REE and fatigue in arm 5, a decrease of IL-6 in arms 3 and 5, and a decrease of TNF-α in arms 3 and 4. As for toxicity, 1 patient discontinued MPA because of deep vein thrombosis and 1 patient discontinued L-carnitine because of severe diarrhoea. In conclusion, the interim results seem to suggest that the most effective treatment for cancer patients with CACS/oxidative stress (OS) should be the combination regimen. The study is in progress.